(Received for publication, April 10, 1996, and in revised form, May 29, 1996)

Tomer Avidor-Reiss , Igal Nevo , Rivka Levy , Thomas Pfeuffer ^§ and Zvi Vogel

From the  Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel and the ^§ Department of Physiological Chemistry II, University of Düsseldorf, Düsseldorf, D-40225 Germany

It has been known for some time that chronic treatment of neuronal cells and tissues with opioids, contrary to their acute effect, leads to an increase in cAMP accumulation. This phenomenon, defined as adenylyl cyclase superactivation, has been implicated in opiate addiction, yet the mechanism by which it is induced remains unclear. Here, we show that this phenomenon can be reproduced and studied in COS-7 cells cotransfected with adenylyl cyclase type V and µ-opioid receptor cDNAs. These cells display acute opioid inhibition of adenylyl cyclase activity, whereas prolonged exposure to the µ-agonist morphine or [-Ala², N-methyl-Phe⁴, Gly-ol⁵]enkephalin leads to a time-dependent superactivation of adenylyl cyclase. This superactivated state is reversible, because it is gradually lost following agonist withdrawal. Adenylyl cyclase superactivation can be prevented by pertussis toxin pretreatment, indicating the involvement of G_i/o proteins, or by cotransfection with the carboxyl terminus of -adrenergic receptor kinase or with -transducin (scavengers of G dimers), indicating a role for the G protein dimers in adenylyl cyclase superactivation. However, contrary to several other G-dependent signal transduction mechanisms (e.g. the extracellular signal-regulated kinase 2/MAP kinase pathway), adenylyl cyclase superactivation is not affected by the Ras dominant negative mutant N17-Ras.

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